Orexins are hypothalamic neuropeptides that play an important role in the regulation of many physiological behaviours such as arousal, wakefulness, appetite, food intake, cognition, motivated behaviours, reward, mood and stress. Orexin A, also referred to as hypocretin 1, is a peptide composed of 33 amino acids and orexin B, also referred to as hypocretin 2, is a peptide composed of 28 amino acids. Both are derived from a common precursor peptide referred to as pre-pro-orexin [Sakurai et al., Cell, 1998 Feb. 20; 92(4):573-85, and De Lecea et al., Proc. Nat. Acad. Sci., 1998 Jan. 6; 95(1):322-7). Orexins bind to two orphan G-protein-coupled receptors, the orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R), which are widely distributed in the central nervous system and peripheral organs such as adrenal glands, gonads, and gut. Whereas orexin A binds predominantly to OX1R, orexin B is able to bind to both OX1R and OX2R.
Orexins are involved in the regulation of a wide range of behaviours including for example the regulation of emotion and reward, cognition, impulse control, regulation of autonomic and neuroendocrine functions, arousal, vigilance and sleep-wakefulness states (Muschamp et al., Proc. Natl. Acad. Sci. USA 2014 Apr. 22; 111(16):E1648-55; for a recent review see Sakurai, Nat. Rev. Neurosci., 2014; November; 15(11):719-31; Chen et al., Med. Res. Rev., 2015; January; 35(1):152-97; Gotter et al., Pharmacol. Rev., 2012, 64:389-420 and many more).
Dual antagonism of OX1R and OX2R by small molecules is clinically efficacious in the treatment of insomnia, for which the drug suvorexant, [[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone] has been granted marketing authorisation (Kishi et al., PLoS One, 2015; 10(8):e0136910). The sleep-inducing effects of dual orexin receptor antagonists are predominantly mediated via OX2R (Bonaventure et al., J. Pharmacol. Exp. Ther., March 2015, 352, 3, 590-601), whereas the other physiological states such as emotion and reward, cognition, impulse control, regulation of autonomic and neuroendocrine functions, arousal, and vigilance are rather mediated via OX1R.
Due to their sleep-inducing effects, dual OX1R and OX2R antagonists are not suitable for treating disorders related to impulse control deficits as seen in addictions such as substance use disorders, personality disorders, such as borderline personality disorder, eating disorders such as binge eating disorder or attention deficit hyperactivity disorder. Therefore, it is desirable to provide an OX1R selective antagonist for the treatment of impulse control deficits.
Neuroimaging with Positron Emission Tomography (PET) ligands is a non-invasive clinical methodology that is frequently used to quantify the concentration of drugs reaching the pharmacological target, as it provides a direct measure of Receptor Occupancy (RO). In addition, PET ligands can be used to assess disease stage and progression as well as for patient stratification.
A PET ligand can be used in RO studies preclinically and clinically in order to support dose finding and generate a brain receptor occupancy plasma concentration relationship for clinical development. PET ligands are labelled with short-lived positron emitting radionuclides such as 11C or 18F. Diverse reagents are available for the introduction of positron-emitting radionuclides and are described for example by P. W. Miller et al. in Angewandte Chemie (International Ed.) 2008, 47, 8998-9033.
A biomathematical modeling approach (Guo et al, The Journal of Nuclear Medicine 2009, 50, 10 1715-1723) has the potential to predict the in vivo performance of compounds based on in silico and in vitro data and aid in the development of molecular imaging probes.
Physicochemical properties as described by L. Zhang et al. (J. Med. Chem. 2013, 56, 4568-4579) can be used to prioritize and accelerate the identification of PET ligands. Compounds suitable for OX1R PET ligand development need to be highly potent at OX1R and at least 100 fold selective over OX2R to ensure specific binding to the OX1R. The log P should be <4 in order to ensure sufficient unbound concentration in the brain. Further in vitro parameters to predict brain exposure is efflux assessed by MDCK efflux measurements. The clearance of a PET ligand should be high, therefore metabolic stability in human liver microsomes should be low.
Orexin receptor antagonists of various structural classes are reviewed in Roecker et al. (J. Med. Chem. 2015, 59, 504-530). WO03/051872, WO2013/187466, WO2016/034882 and Bioorganic & Medicinal Chemistry 2015, 23, 1260-1275 describe orexin receptor antagonists.